Lisa J Martin1, Hua He2, Margaret H Collins3, J Pablo Abonia4, Joceyln M Biagini Myers5, Michael Eby6, Hanna Johansson7, Leah C Kottyan8, Gurjit K Khurana Hershey5, Marc E Rothenberg9. 1. Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati Medical School, Cincinnati, Ohio. 2. Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 3. Department of Pediatrics, University of Cincinnati Medical School, Cincinnati, Ohio; Division of Pathology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 4. Department of Pediatrics, University of Cincinnati Medical School, Cincinnati, Ohio; Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 5. Department of Pediatrics, University of Cincinnati Medical School, Cincinnati, Ohio; Division of Asthma Research, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 6. Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 7. Division of Asthma Research, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 8. Department of Pediatrics, University of Cincinnati Medical School, Cincinnati, Ohio; Center for Autoimmune Genomics and Etiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 9. Department of Pediatrics, University of Cincinnati Medical School, Cincinnati, Ohio; Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address: marc.rothenberg@cchmc.org.
Abstract
BACKGROUND: Eosinophilic esophagitis (EoE) is an esophageal inflammatory disease associated with atopic diseases. Thymic stromal lymphopoietin (TSLP) and calpain 14 (CAPN14) genetic variations contribute to EoE, but how this relates to atopy is unclear. OBJECTIVE: The purpose of this study was to explore the relationship between EoE, atopy, and genetic risk. METHODS: EoE-atopy enrichment was tested by using 700 patients with EoE and 801 community control subjects. Probing 372 single nucleotide polymorphisms (SNPs) in 63 atopy genes, we evaluated EoE associations using 412 nonatopic and 868 atopic disease control subjects. Interaction and stratified analyses of EoE-specific and atopy-related SNPs were performed. RESULTS: Atopic disease was enriched in patients with EoE (P < .0001). Comparing patients with EoE and nonatopic control subjects, EoE associated strongly with IL-4/kinesin family member 3A (IL4/KIF3A) (P = 2.8 × 10-6; odds ratio [OR], 1.87), moderately with TSLP (P = 1.5 × 10-4; OR, 1.43), and nominally with CAPN14 (P = .029; OR, 1.35). Comparing patients with EoE with atopic disease control subjects, EoE associated strongly with ST2 (P = 3.5 × 10-6; OR, 1.77) and nominally with IL4/KIF3A (P = .019; OR, 1.25); TSLP's association persisted (P = 4.7 × 10-5; OR, 1.37), and CAPN14's association strengthened (P = .0001; OR, 1.71). Notably, there was gene-gene interaction between TSLP and IL4 SNPs (P = .0074). Children with risk alleles for both genes were at higher risk for EoE (P = 2.0 × 10-10; OR, 3.67). CONCLUSIONS: EoE genetic susceptibility is mediated by EoE-specific and general atopic disease loci, which can have synergistic effects. These results might aid in identifying potential therapeutics and predicting EoE susceptibility.
BACKGROUND:Eosinophilic esophagitis (EoE) is an esophageal inflammatory disease associated with atopic diseases. Thymic stromal lymphopoietin (TSLP) and calpain 14 (CAPN14) genetic variations contribute to EoE, but how this relates to atopy is unclear. OBJECTIVE: The purpose of this study was to explore the relationship between EoE, atopy, and genetic risk. METHODS: EoE-atopy enrichment was tested by using 700 patients with EoE and 801 community control subjects. Probing 372 single nucleotide polymorphisms (SNPs) in 63 atopy genes, we evaluated EoE associations using 412 nonatopic and 868 atopic disease control subjects. Interaction and stratified analyses of EoE-specific and atopy-related SNPs were performed. RESULTS:Atopic disease was enriched in patients with EoE (P < .0001). Comparing patients with EoE and nonatopic control subjects, EoE associated strongly with IL-4/kinesin family member 3A (IL4/KIF3A) (P = 2.8 × 10-6; odds ratio [OR], 1.87), moderately with TSLP (P = 1.5 × 10-4; OR, 1.43), and nominally with CAPN14 (P = .029; OR, 1.35). Comparing patients with EoE with atopic disease control subjects, EoE associated strongly with ST2 (P = 3.5 × 10-6; OR, 1.77) and nominally with IL4/KIF3A (P = .019; OR, 1.25); TSLP's association persisted (P = 4.7 × 10-5; OR, 1.37), and CAPN14's association strengthened (P = .0001; OR, 1.71). Notably, there was gene-gene interaction between TSLP and IL4 SNPs (P = .0074). Children with risk alleles for both genes were at higher risk for EoE (P = 2.0 × 10-10; OR, 3.67). CONCLUSIONS: EoE genetic susceptibility is mediated by EoE-specific and general atopic disease loci, which can have synergistic effects. These results might aid in identifying potential therapeutics and predicting EoE susceptibility.
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